Polymorphs of tolterodine tartrate

ABSTRACT

The present invention relates to novel polymorphs of tolterodine tartrate, to processes for their preparation and to pharmaceutical compositions containing them.

FIELD OF THE INVENTION

This application is a 371 of PCT/IN03/00149 filed 8 Apr. 2003.

The present invention relates to novel polymorphs of tolterodinetartrate, to processes for their preparation and to pharmaceuticalcompositions containing them.

BACKGROUND OF THE INVENTION

Tolterodine of formula (1):

or 2-[(1R)-3-[bis(1-methylethyl)amino]-1-phenylpropyl]-4-methylphenoland its salts are muscarinic receptor antagonists. Tolterodine tartrateis a muscarinic receptor antagonist and is used in the treatment ofurinary incontinence. Tolterodine tartrate and related compounds andtheir therapeutic uses are disclosed in EP 0325571.

Polymorphs of tolterodine tartrate were not reported in the literature.So, there is a need for stable, well-defined and reproduciblecrystalline forms.

It has now been discovered that tolterodine tartrate can be prepared infour well-defined and consistently reproducible crystalline forms andone stable amorphous form.

The object of the present invention is to provide stable novelpolymorphs of tolterodine tartrate, processes for preparing these formsand pharmaceutical compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a novelcrystalline form of tolterodine tartrate, designated as form I,characterized by an x-ray powder diffraction spectrum having peaksexpressed as 2θ at about 11.9, 13.6, 14.2, 15.9, 16.9, 18.4, 18.8, 20.4,22.0, 23.9, 25.4, 26.3 and 29.8 degrees. FIG. 1 shows typical form Ix-ray powder diffraction spectrum.

In accordance with the present invention, a process is provided forpreparation of tolterodine tartrate form I. Thus, tolterodine free baseis dissolved in a suitable solvent, tartaric acid is added to thesolution and tolterodine tartrate form I is isolated. The suitablesolvents are ethanol, methylene dichloride, chloroform, acetone,acetonitrile and 1,4-dioxane; and a mixture thereof. The preferablesolvents are ethanol and acetone.

In accordance with the present invention, there is provided a novelcrystalline form of tolterodine tartrate, designated as form II,characterized by an x-ray powder diffraction spectrum having peaksexpressed as 2θ at about 8.7, 9.0, 9.6, 10.1, 10.4, 11.9, 14.0, 15.7,16.9, 17.6, 17.9, 18.4, 18.7, 20.0, 20.5, 22.1, 24.5, 29.1 and 35.9degrees. FIG. 2 shows typical form II x-ray powder diffraction spectrum.

In accordance with the present invention, a process is provided forpreparation of tolterodine tartrate form II. Thus, tolterodine free baseis dissolved in ethyl acetate, tartaric acid is added and tolterodinetartrate form II is isolated by filtration or centrifugation.

In accordance with the present invention, there is provided a novelcrystalline form of tolterodine tartrate, designated as form III,characterized by an x-ray powder diffraction spectrum having peaksexpressed as 2θ at about 9.1, 9.7, 10.6, 11.7, 11.9, 12.7, 14.3, 15.7,17.9, 18.5, 18.8, 19.1, 20.1, 20.4, 22.1, 22.5, 25.1, 32.8 and 35.5degrees. FIG. 3 shows typical form III x-ray powder diffractionspectrum.

In accordance with the present invention, a process is provided forpreparation of tolterodine tartrate form III. Thus, tolterodine freebase is dissolved in methyl tert-butyl ether, tartaric acid is added tothe solution and tolterodine tartrate form III is isolated by filtrationor centrifugation.

In accordance with the present invention, there is provided a novelcrystalline form of tolterodine tartrate, designated as form IV,characterized by an x-ray powder diffraction spectrum having peaksexpressed as 2θ at about 7.8, 9.8, 15.2, 17.2, 17.7, 18.4, 18.9, 20.3and 25.9 degrees. FIG. 4 shows typical form IV x-ray powder diffractionspectrum.

In accordance with the present invention, a process is provided forpreparation of tolterodine tartrate form IV. Thus, tolterodine tartrate,an alcohol and water are mixed and the solvents are removed from thesolution by freeze drying. The suitable alcohols are methanol, ethanol,isopropyl alcohol and n-butanol; and a mixture thereof. The preferablealcohols are methanol and ethanol.

In accordance with the present invention, there is provided a novelamorphous form of tolterodine tartrate, designated as amorphoustolterodine tartrate, characterized by having broad x-ray diffractionspectrum as in FIG. 5.

In accordance with the present invention, a process is provided forpreparation of amorphous tolterodine tartrate. Thus, tolterodinetartrate, an alcohol and water are mixed and the solvents are removedfrom the solution by vacuum drying or spray drying. The suitablealcohols are methanol, ethanol, isopropyl alcohol and n-butanol; and amixture thereof. The preferable alcohol are methanol and ethanol.

Tolterodine free base and tolterodine tartrate used in the aboveprocesses can be obtained from the previously known methods.

In accordance with the present invention, there is provided apharmaceutical composition comprising a polymorphic form of tolterodinetartrate and pharmaceutically acceptable carrier or diluent. Thepolymorphic form includes form I, form II, form III, form IV oramorphous tolterodine tartrate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a x-ray powder diffraction spectrum of tolterodine tartrateform I.

FIG. 2 is a x-ray powder diffraction spectrum of tolterodine tartrateform II.

FIG. 3 is a x-ray powder diffraction spectrum of tolterodine tartrateform III.

FIG. 4 is a x-ray powder diffraction spectrum of tolterodine tartrateform IV.

FIG. 5 is a x-ray powder diffraction spectrum of amorphous tolterodinetartrate.

x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-raypowder diffractometer having a copper-Kα radiation.

The following examples further illustrate the present invention.

EXAMPLE 1

Tolterodine free base (5.0 gm) is dissolved in ethanol (75 ml) andtartaric acid (3.0 gm) is added to the solution. Then the contents arestirred for 2 hours at 25° C. to 30° C. and filtered to give 5.0 gm oftolterodine tartrate form I.

EXAMPLE 2

Tolterodine free base (5.0 gm) is dissolved in acetone (80 ml) andtartaric acid (3.0 gm) is added to the solution. Then the contents arestirred for 2 hours at 25° C. to 30° C. and filtered to give 5.0 gm oftolterodine tartrate form I.

EXAMPLE 3

Tolterodine free base (2.0 gm) is dissolved in ethyl acetate (25 ml) andtartaric acid (1.2 gm) is added to the solution. Then the contents aremaintained for 2 hours at 25° C. to 30° C. and filtered to give 2.2 gmof tolterodine tartrate form II.

EXAMPLE 4

Tolterodine free base (2.0 gm) is dissolved in methyl tert-butyl ether(25 ml), tartaric acid (1.2 gm) is added and the reaction mass is heatedto 40° C. Then the contents are cooled to 25° C., maintained for 2 hoursat 25° C. to 30° C. and filtered to give 2.1 gm of tolterodine tartrateform III.

EXAMPLE 5

Tolterodine tartrate (2.0 gm), methanol (50 ml) and water (50 ml) aremixed. The solution is subjected to freeze drying for 20 hours to give1.9 gm of tolterodine tartrate form IV.

EXAMPLE 6

Tolterodine tartrate (2.0 gm), ethanol (50 ml) and water (50 ml) aremixed. The solution is subjected to freeze drying for 20 hours to give1.9 gm of tolterodine tartrate form IV.

EXAMPLE 7

Example 5 is repeated using tolterodine tartrate form I instead oftolterodine tartrate. The yield of tolterodine tartrate form IV is 1.9gm.

EXAMPLE 8

Tolterodine tartrate (2.0 gm), methanol (50 ml) and water (50 ml) aremixed. The solvents are removed from the solution by vacuum drying for10 hours at 60° C. to give 1.8 gm of amorphous tolterodine tartrate.

EXAMPLE 9

Example 8 is repeated using tolterodine tartrate form II instead oftolterodine tartrate. The yield of amorphous tolterodine tartrate is 1.8gm.

EXAMPLE 10

Tolterodine tartrate (2.0 gm), methanol (50 ml) and water (50 ml) aremixed. The solution is subjected to spray drying in a Mini-Spray Dryer(Buchi Model-190) at an inlet temperature 89° C.-91° C. and outlettemperature 61° C.-42° C. to give 1.7 gm of amorphous tolterodinetartrate.

1. A crystalline tolterodine tartrate form I, characterized by an x-raypowder diffraction spectrum having peaks expressed as 2θ at about 11.9,13.6, 14.2, 15.9, 16.9, 18.4, 18.8, 20.4, 22.0, 23.9, 25.4, 26.3 and29.8 degrees.
 2. The crystalline tolterodine tartrate form I as definedin claim 1, further characterized by an x-ray powder diffractionspectrum as in FIG.
 1. 3. The process for preparation of tolterodinetartrate form 1 as defined in claim 1, which comprises the steps of: a)dissolving tolterodine free base in a suitable solvent; b) addingtartaric acid; and c) isolating tolterodine tartrate form I; wherein thesuitable solvent is selected from the group consisting of ethanol,methylene dichloride, chloroform, acetone, acetonitrile and 1,4-dioxane.4. The process according to claim 3, wherein the suitable solvent isethanol.
 5. The process according to claim 3, wherein the suitablesolvent is acetone.
 6. A crystalline tolterodine tartrate form II,characterized by an x-ray powder diffraction spectrum having peaksexpressed as 2θ at about 8.7, 9.0, 9.6, 10.1, 10.4, 11.9, 14.0, 15.7,16.9, 17.6, 17.9, 18.4, 18.7, 20.0, 20.5, 22.1, 24.5, 29.1 and 35.9degrees.
 7. The crystalline tolterodine tartrate form II as defined inclaim 6, further characterized by an x-ray powder diffraction spectrumas in FIG.
 2. 8. The process for preparation of tolterodine tartrateform II as defined in claim 6, which comprises the steps of: a)dissolving tolterodine free base in ethyl acetate; b) adding tartaricacid; and c) isolating tolterodine tartrate form II.
 9. A crystallinetolterodine tartrate form III, characterized by an x-ray powderdiffraction spectrum having peaks expressed as 2θ at about 9.1, 9.7,10.6, 11.7, 11.9, 12.7, 14.3, 15.7, 17.9, 18.5, 18.8, 19.1, 20.1, 20.4,22.1, 22.5, 25.1, 32.8 and 35.5 degrees.
 10. The crystalline tolterodinetartrate form III as defined in claim 9, further characterized by anx-ray powder diffraction spectrum as in FIG.
 3. 11. The process forpreparation of tolterodine tartrate form III as defined in claim 9,which comprises the steps of: a) dissolving tolterodine free base inmethyl tert-butyl ether; b) adding tartaric acid; and c) isolatingtolterodine tartrate form III.
 12. A crystalline tolterodine tartrateform IV, characterized by an x-ray powder diffraction spectrum havingpeaks expressed as 2θ at about 7.8, 9.8, 15.2, 17.2, 17.7, 18.4, 18.9,20.3 and 25.9 degrees.
 13. The crystalline tolterodine tartrate form IVas defined in claim 12, further characterized by an x-ray powderdiffraction spectrum as in FIG.
 4. 14. The process for preparation oftolterodine tartrate form IV as defined in claim 12, which comprises thesteps of: a) mixing tolterodine tartrate, an alcohol and water; and b)removing the solvents from the solution formed in step (a) by freezedrying; wherein the alcohol is selected from the group consisting ofmethanol, ethanol, isopropyl alcohol and n-butanol.
 15. The processaccording to claim 14, wherein the suitable alcohol is methanol.
 16. Theprocess according to claim 14, wherein the suitable alcohol is ethanol.17. Amorphous tolterodine tartrate characterized by an x-ray powderdiffraction spectrum as in FIG.
 5. 18. The process for preparation ofamorphous tolterodine tartrate as defined in claim 17, which comprisesthe steps of: a) mixing tolterodine tartrate, an alcohol and water; andb) removing the solvents from the solution formed in step (a) by vacuumdrying or by spray drying; wherein the alcohol is selected from thegroup consisting of methanol, ethanol, isopropyl alcohol and n-butanol.19. The process according to claim 18, wherein the suitable alcohol ismethanol.
 20. The process according to claim 18, wherein the suitablealcohol is ethanol.
 21. The process according to claim 18, wherein thesolvents are removed by vacuum drying.
 22. The process according toclaim 18, wherein the solvents are removed by spray drying.
 23. Apharmaceutical composition comprising a polymorphic form of tolterodinetartrate and a pharmaceutically acceptable carrier or diluent.
 24. Apharmaceutical composition comprising a polymorphic form of tolterodinetartrate as claimed in claim 1 and a pharmaceutically acceptable carrieror diluent.
 25. A pharmaceutical composition comprising a polymorphicform of tolterodine tartrate as claimed in claim 6 and apharmaceutically acceptable carrier or diluent.
 26. A pharmaceuticalcomposition comprising a polymorphic form of tolterodine tartrate asclaimed in claim 9 and a pharmaceutically acceptable carrier or diluent.27. A pharmaceutical composition comprising a polymorphic form oftolterodine tartrate as claimed in claim 12 and a pharmaceuticallyacceptable carrier or diluent.
 28. A pharmaceutical compositioncomprising a polymorphic form of tolterodine tartrate as claimed inclaim 17 and a pharmaceutically acceptable carrier or diluent.